Key message
Most international guidelines recommend amitriptyline, duloxetine, pregabalin or gabapentin for the treatment of neuropathic pain in diabetic patients (DPNP – Diabetic Peripheral Neuropathic Pain). If the monotherapy is insufficiently effective, it is often recommended to add a second molecule, a common practice despite the lack of evidence.
From OPTION-DM-studies (Optimal Pathway for TreatIng NeurOpathic paiN in Diabetes Mellitus) is the first randomized, methodologically strong, study to investigate and compare the efficacy of three combination treatments. That study shows that the three combinations provide comparable pain relief in diabetic neuropathy. When the pain is not sufficiently controlled with monotherapy, the combinations provide stronger analgesia.
Why is this study important?
The most common neuropathy in the general population is symmetrical and mixed sensorimotor neuropathy. This polyneuropathy is more common in type 2 diabetes (8%-25%) than in type 1 diabetes, and its frequency increases with age and disease duration: 42% after 10 years and 50% after 25 years. About 50% of patients with diabetic polyneuropathy will experience neuropathic pain, and in half of these patients it will affect sleep, quality of life and mood.
As the first-line treatment of DPNP, the guidelines recommend amitriptyline (a tricyclic antidepressant), duloxetine (a serotonin and noradrenaline reuptake inhibitor), pregabalin, or gabapentin (two antiepileptic drugs). In monotherapy, these drugs provide, at best, a 50% reduction in pain in 50% of patients. The treatment of DPNP clearly has its limitations.
Design of the study
The patients included in the study mostly had type 2 diabetes (more than 80%) and had neuropathic pain complaints on a daily basis for at least three months (see ‘more info’).
OPTION-DM is a controlled, randomized, double-blind, three-arm crossover study:
amitriptyline, if necessary supplemented with pregabalin (AP),
pregabalin, if necessary supplemented with amitriptyline (PA),
duloxetine, supplemented with pregabalin (DP) if necessary.
Each treatment strategy was evaluated sequentially for a total of 51 weeks (see ‘more info’).
The primary endpoint was the difference between the three treatment strategies in pain intensity, measured during the last week before switching to another treatment path. The pain was measured on the NRS (see ‘more info’).
The secondary endpoints included the difference between the monotherapies in the NRS, measured during the last week before any switch to combination therapy, the quality of life measured by the SF-36, the anxiety and depression measured by the HADS, and the severity of insomnia measured with the ISI (see ‘more info’ for an explanation of the scales).
- Study population :
- 130 patients: 17% (22 patients) with type 1 diabetes and more than 80% with type 2 diabetes
- neuropathic pain in the hands and/or feet for at least three months
- bilateral, symmetrical distal polyneuropathy, confirmed by mTCNS (modified Toronto Clinical Neuropathy Score)
- bilateral and symmetrical distal neuropathic pain, confirmed with the DN4 (Douleur Neuropathique 4 Questionnaire)
- pain intensity on the NRS ≥ 4 for a week, after discontinuation of all drugs
- The study lasted a total of 51 weeks. Each course of treatment lasted 16 weeks, with a washout period of 1 week between each course. The study started with a 2-week titration phase to reach the maximum tolerated dose.
- The dose of the treatments was increased to a maximum of 75 mg per day for amitriptyline, 120 mg per day for duloxetine and 600 mg per day for pregabalin.
- In each trajectory, patients received monotherapy for the first six weeks. If the pain was not sufficiently controlled after those six weeks (NRS higher than 3 in the sixth week), the treatment was supplemented with the second molecule for the next ten weeks.
- NRS (Numerical Rating Scale): numerical scale for self-assessment of pain intensity with 11 levels, ranging from 0 (no pain) to 10 (worst pain imaginable). The reported NRS is the average of the NRS scores measured daily during the week in question.
- Measurement scales used to evaluate the secondary endpoints:
- SF-36 (36 item Short Form Survey): standardized test that measures quality of life based on a questionnaire. A high score corresponds to a better health status.
- HADS (Hospital Anxiety and Depression Scale): questionnaire with 14 items (score of 0 to 3 per item) for the detection of anxiety disorders and depression. The higher the score, the higher the chance that the patient suffers from anxiety and depression.
- ISI (Insomnia Severity Index): 7-item questionnaire for insomnia self-assessment: satisfaction with sleep pattern, daily functioning, and anxiety caused by the sleep problem. The total score varies between 0 (no insomnia) and 28 (severe insomnia.
Results in short
Of the 140 patients randomly assigned to the six treatment sequences, 130 were included in the analysis: 130 entered a first trajectory, 97 a second trajectory, and 84 a third trajectory. Their average age was 62 years.
With regard to the primary endpoint, there was no significant difference between the three treatment strategies: the mean NRS decreased from 6.6 at the start of the study to 3.3 at the end of each trajectory.
The combination treatments provide additional pain reduction between weeks 6 and 16 compared to monotherapy (difference in NRS reduction between combination and monotherapy of 0.8).
35% of patients achieved pain relief (NRS ≤ to 3) with monotherapy, and an additional 18% of patients achieved pain relief with the addition of a second molecule.
When comparing the NRS measured during monotherapy, no difference was seen between the different treatments in monotherapy. The NRS at week 6 was similar across the 3 trajectories.
The scores for quality of life, depression/anxiety and sleep indicated an improvement in all three pathways, but the clinical relevance of these results is unclear.
The known adverse effects of the investigated treatments were commonly observed in the OPTION-DM study: dizziness in the PA group, dry mouth in the AP group, and nausea in the DP group. There was no significant difference in the frequency of serious adverse events between the different treatment pathways.
Commentary from the BCFI
The small number of patients who reached the end of the study is a major limitation of the study. Only 59% of patients completed the three treatment courses and only 64% completed two treatment courses. The results of the study should therefore be interpreted with caution. Given the high failure rate, we may wonder to what extent the combination therapies are well tolerated.
The authors have chosen the investigated molecules from a pragmatic point of view, which strongly limits the data we can extract from the study results (see ‘more info’).
Another treatment strategy, not used here, is that of sequential monotherapy (switching from one monotherapy to another monotherapy before switching to a combination treatment).
The lack of a placebo group is a limitation of this study, but the addition of a placebo group would have further extended the already long study duration. In addition, it would be ethically difficult to justify not giving a treatment that is considered first choice in the guidelines (NeuPSIG and NICE).
The effectiveness of the proposed and investigated combinations can be explained, among other things, by the different mechanisms of action of these drugs, which complement each other to a certain extent.
The study confirms that the drugs recommended in the guidelines have comparable efficacy in monotherapy.
- There are other combinations that could have been evaluated :
- The choice of amitriptyline in this study is guided by the guidelines, which recommend it as the first choice for neuropathic pain in adults. Other tricyclic antidepressants are also available and could have been evaluated as well.
- The combination ‘pregabalin first and then duloxetine’ has not been studied because the results of the COMBO-DN study were not convincing (see below). The duloxetine-pregabalin combination, on the other hand, was included in the study because duloxetine is taken once a day and is less expensive in the United Kingdom, which is also the case in Belgium.
- Gabapentin has not been evaluated for practical reasons: multiple intakes (3x/d), long titration period (2 months) to avoid toxicity and same therapeutic class as pregabalin.
- COMBO-DN study (COmbination vs. Monotherapy of pregabalin and dulOxetine in Diabetic Neuropathy): Previously published RCT in which it was shown that adding pregabalin to duloxetine (or vice versa) had no benefit on pain reduction.
Conclusion
Certain drug combinations have been shown to have an additive effect in diabetic patients with neuropathic pain inadequately controlled on monotherapy.
This study shows that the drugs studied have comparable efficacy, both in monotherapy and in combination. The choice for a particular drug could therefore be made on the basis of the profile of the patient and his comorbidities, the possible undesirable effects and the cost price of the drug, rather than on the basis of its efficacy.
Sources
– Tesfaye S, Sloan G, Petrie J et al. Comparison of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin for the treatment of diabetic peripheral neuropathic pain (OPTION-DM): a multicentre, double-blind, randomised crossover trial, The Lancet 2022;400:680-90 (doi.org/10.1016/S0140-6736(22)01472-6)
– Elafros MA, Callaghan BC. Effective treatment pathways exist for DPNP, The Lancet 2022; 400:639-641 (doi.org/10.1016/ S0140-6736(22)01526-4)
– Finnerup N, Attal N, Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations, Lancet Neurol. 2015;14(2): 162–173 (doi:10.1016/S1474-4422(14)70251-0)
– NICE : Neuropathic pain in adults: pharmacological management in non-specialist settings, www.nice.org.uk/guidance/cg173
– Tesfaye S, Wilhelm S, Lledo A, et al. Duloxetine and pregabalin: high-dose monotherapy or their combination? The ‘‘COMBO-DN study’’ – a multinational, randomized, double-blind, parallel-group study in patients with diabetic peripheral neuropathic pain. Pain 2013;154:2616–2625 (doi.org/10.1016/j.pain.2013.05.043)
– Selvarajah D, Petrie J, White D et al. Multicentre, double-blind, crossover trial to identify the Optimal Pathway for TreatIng neurOpathic paiN in Diabetes Mellitus (OPTION-DM) : study protocol for a randomized controlled trial. Trials. 2018; 19:578